Lecture 8: Adrenal Corticosteroids Flashcards
What is most of the endogenous cortisol found bound to in the serum; how does this differ for biologically active cortisol?
- Bound to proteins, corticosteroid-binding globulin (CBG) and albumin
- Biologically active cortisol may be bound to erythrocytes
How do synthetic steroids differ from endogenous types in terms of binding to proteins in circulation?
- Synthetic steroids other than prednisolone either bind weakly to albumin (2/3’s)
or
- Circulate as free steroid (1/3)
In which tissues is the type 2 isoenzyme of 11β-hydroxysteroid-dehydrogenase found and what is its function?
- Found mainly in mineralocorticoid target tissues (kidney, colon, salivary glands)
and
- The placenta, in which it protects the cell from cortisol activation of the corticosteroid type 1 (mineralocorticoid) receptor
Why does prednisone have less salt-retaining activity compared to cortisol?
Prednison is more effectively oxidized by 11β-hydroxysteroid-dehydrogenase type 2
Which CYP is responsible for the metabolism of synthetic and natural glucocorticoids?
CYP3A4
How does the 11β-hydroxysteroid-dehydrogenase type 1 vs. type 2 isoenzyme differ in their action on steroids?
- Type 2 converts active steroids –> inert forms
- Type 1 converts inert steroids –> active forms
What are the active forms of cortisone, 11-dehydrocorticosterone, and prednisone; which enzyme activates them?
- Cortisone —> cortisol (active)
- 11-dehydrocorticosterone –> corticosterone (active)
- Prednisone —> prednisolone (active)
*All due to 11β-hydroxysteroid-dehydrogenase type 1*
What are known inhibitors of 11β-hydroxysteroid-dehydrogenase type 2?
- Glycyrrhizin (licorice root extract)
- Carbenoxolone (UK approved for Rx-esophageal ulcers)
What is the downstream effect following inhibition of 11β-hydroxysteroid-dehydrogenase type 2 by substances such as glycyrrhizin (licorice root extract)?
↑ activity cortisol 2 MR –> ↑ Na+ and H2O retention, ↑ K+ loss –> ↑ BP
List 5 ways that glucocorticoids effect the immune system and inlammation
- ↓ production of prostaglandins and leukotrienes
- ↓ production and ↑ apoptosis of immune cell types
- ↓ production of cytokines + their receptors
- ↓ transmigration of neutrophils and macrophages from blood –> tissue
- ↓ expression of cell adhesion molecules
Which combination of corticosteroids can be given for primary adrenal insufficiency and congenital adrenal hyperplasia?
Hydrocortisone + Fludrocortisone
List the 5 short to medium acting glucocorticoids (<12 hours)?
- Hydrocortisone (cortisol)
- Cortisone
What is the intermediate-acting (12-36 hour) glucocorticoid?
Triamcinolone
Prednisone
Prednisolone
Methylprednisolone
List the 2 long-acting (>36 hours) glucocorticoids.
- Betamethasone
- Dexamethasone
List 7 AE’s associated with prednisolone use.
- Adrenal suppression
- Growth inhibition
- Muscle wasting
- Osteoporosis
- Salt retention
- Glucose intolerance
- Behavioral changes
Which drug is a glucocorticoid receptor antagonist and which receptors does it act on?
- Mifepristone
- Antagonist of glucocorticoid and progesterone receptors
What are the clinical uses of Mifepristone?
- Medical abortion
- Very rarely for Cushing’s Syndrome
Which 2 corticosteroids have the most potent anti-inflammatory activity and are available in a topical formula?
- Prednisolone
- Methylprednisolone
Of the long-acting corticosteroids which is the most potent anti-inflammatory drug?
Dexamethasone
What is the name of the mineralocorticoid agonist used clincially and what is its anti-inflammatory vs. salt-retaining potency like?
- Fludrocortisone
- Mild anti-inflammatory potency w/ ↑↑↑ salt-retaining activity
List the AE’s associated with mifepristone.
- Vaginal bleeding in women
- Abdominal pain + GI upset
- Diarrhea
- HA
What is the clinical application for Fludrocortisone?
Adrenal insufficiency (Addison’s disease)
What is the duration of action like for Fludrocortisone?
Long
What are 3 AE’s associated with Fludrocortisone?
- Salt and fluid retention
- CHF
- Signs and sx’s of glucocorticoid excess
What is the name of the mineralocorticoid receptor antagonist?
Spironolactone
What are the clinical applications of Spironolactone?
- Hyperaldosteronism from any cause
- Hypokalemia due to diuretic effect
- Post-MI
What is the onset of action and duration like for Spironolactone?
Slow onset and offset; duration = 24-48 hrs
What are the AE’s and drug-interactions associated with Spironolactone?
- HYPERkalemia
- Gynecomastia
- Additive interaction w/ other K+ retaining drugs
